2-氯-9-(5-O-膦酰-beta-D-来苏呋喃糖基)-9H-嘌呤-6-胺 | 21466-01-3

• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 嘌呤核苷酸
• 中文名称: 2-氯-9-(5-O-膦酰-beta-D-来苏呋喃糖基)-9H-嘌呤-6-胺
• 英文名称: phosphoric acid mono[(2R,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-ylmethyl]ester
• 英文别名: 9-(β-D-ribofuranosyl)-2-chloroadenine 5'-monophosphate；2-chloroadenosine 5'-phosphate；PF1；2-Cl-AMP；2-chloro-[5']adenylic acid；2-Chloradenosin-5'-monophosphat；2-Chloro-adenosine monophosphate；[(2R,3S,4R,5R)-5-(6-amino-2-chloropurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methyl dihydrogen phosphate
• CAS: 21466-01-3
• 化学式: C₁₀H₁₃ClN₅O₇P
• 分子量: 381.669
• InChiKey: FXXRIUZMLRLFKP-UUOKFMHZSA-N

物化性质

• 熔点：
  >95°C (dec.)
• 溶解度：
  可溶于甲醇；水

计算性质

• 辛醇/水分配系数(LogP)：
  -2.6
• 重原子数：
  24
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  186
• 氢给体数：
  5
• 氢受体数：
  11

反应信息

• 作为反应物：
  描述：

  2-氯-9-(5-O-膦酰-beta-D-来苏呋喃糖基)-9H-嘌呤-6-胺 在 三正丁胺 、 N,N'-羰基二咪唑 、 tris(tributylammonium) phosphate 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 14.0h， 以39%的产率得到[[(2R,3R,4R,5R)-5-(6-氨基-2-氯-嘌呤-9-基)-3,4-二羟基-四氢呋喃-2-基]甲氧基-羟基-磷酰]氧基膦酸
  参考文献：
  名称：

  2-ClATP exerts anti-tumoural actions not mediated by P2 receptors in neuronal and glial cell lines

  摘要：

  We investigated the effects of the ATP analogue and P2 receptor agonist 2-ClATP on growth and survival of different neuronal (PC12, PC12nnr5 and SH-SY5Y) and glial (U87 and U373) cell lines, by the use of direct count of intact nuclei, fluorescence microscopy, fluorescence-activated cell sorter analysis (FACS) and high pressure liquid chromatography (HPLC). 2-ClATP lowered the number of cultured PC12nnr5, SH-SY5Y, U87 and U373 cells to almost 5%, and of PC12 cells to about 35% after 3-4 days of treatment. EC50 was in the 5-25 muM range, with 2-ClATP behaving as a cytotoxic or cytostatic agent. Analysis of the biological mechanisms demonstrated that pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (P2 receptor antagonist and nucleotidases inhibitor), but not Caffeine or CGS-15493 (PI receptor antagonists) effectively prevented 2-ClATP-induced toxicity. 2-ClATP metabolic products (2-ClADP, 2-ClAMP, 2-Cladenosine) and new synthesis derivatives (2-CldAMP, 2-Cldadenosine-3',5'-bisphosphate and 2-CldATP) exerted similar cytotoxic actions. Inhibition of both serum nucleotidases and purine nucleoside transporters strongly reduced 2-ClATP-induced cell death, which was conversely increased by the nucleotide hydrolyzing enzyme apyrase. The adenosine kinase inhibitor 5-iodotubericidin totally prevented 2-ClATP or 2-Cladenosine-induced toxicity.In summary, our findings indicate that 2-ClATP exerts either cell cycle arrest or cell death, acting neither on P2 nor on P1 receptors, but being extracellularly metabolized into 2-Cladenosine, intracellularly transported and re-phosphorylated. (C) 2003 Elsevier Inc. All rights reserved.

  DOI：

  10.1016/j.bcp.2003.09.015
• 作为产物：
  描述：

  在 DOWEX 50WX₈-200 作用下， 以 甲醇 、 水 为溶剂， 生成 2-氯-9-(5-O-膦酰-beta-D-来苏呋喃糖基)-9H-嘌呤-6-胺
  参考文献：
  名称：

  Adenine Nucleotide Analogues Locked in a Northern Methanocarba Conformation:  Enhanced Stability and Potency as P2Y₁ Receptor Agonists

  摘要：

  Preference for the Northern (N) ring conformation of the ribose moiety of nucleotide 5'-triphosphate agonists at P2Y(1), P2Y(2), P2Y(4), and P2Y(11) receptors, but not P2Y(6) receptors, was established using a ring-constrained methanocarba (a 3.1.0-bicyclohexane) ring as a ribose substitute (Kim et al. J. Med. Chem. 2002, 45, 208-218.). We have now combined the ring-constrained (N)-methanocarba modification of adenine nucleotides with other functionalities known to enhance potency at P2 receptors. The potency of the newly synthesized analogues was determined in the stimulation of phospholipase C through activation of turkey erythrocyte P2Y, or human P2Y, and P2Y2 receptors stably expressed in astrocytoma cells. An (N)methanocarba-2-methylthio-ADP analogue displayed an EC50 at the hP2Y(1) receptor of 0.40 nM and was 55-fold more potent than the corresponding triphosphate and 16-fold more potent than the riboside 5'-diphosphate. 2-Cl-(N)-methanocarba-ATP and its N-6-Me analogue were also highly selective, full agonists at P2Y, receptors. The (N)-methanocarba-2-methylthio and 2-chloromonophosphate analogues were full agonists exhibiting micromolar potency at P2Y(1) receptors, while the corresponding ribosides were inactive. Although beta,y-methylene-ATP was inactive at P2Y receptors beta,y-methylene-(N)-methanocarba-ATP was a potent hP2Y1 receptor agonist with an EC50 of 160 nM and was selective versus hP2Y(2) and hP2Y(4) receptors. The rates of hydrolysis of Northern (N) and Southern (S) methanocarba analogues of AMP by rat 5'-ectonucleotidase were negligible. The rates of hydrolysis of the corresponding triphosphates by recombinant rat NTPDase 1 and 2 were studied. Both isomers were hydrolyzed by NTPDase 1 at about half the rate of ATP hydrolysis. The (N) isomer was hardly hydrolyzed by NTPDase 2, while the (S) isomer was hydrolyzed at one-third of the rate of ATP hydrolysis. This suggests that new, more stable and selective nucleotide agonists may be designed on the basis of the (N)-conformation, which greatly enhanced potency at P2Y, receptors.

  DOI：

  10.1021/jm010538v

文献信息

• Species- or isozyme-specific enzyme inhibitors. 7. Selective effects in inhibitions of rat adenylate kinase isozymes by adenosine 5'-phosphate derivatives
  作者：Ton T. Hai、Donald Picker、Masanobu Abo、Alexander Hampton

  DOI：10.1021/jm00349a008

  日期：1982.7

  Monosubstituted derivatives of adenosine 5'-phosphate (AMP) with substituents of 1-3 atoms or group replacements at any of 11 positions have been synthesized and examined as substrates and inhibitors of the rat muscle adenylate kinase isozyme (AK-M), and the rat AK II and III isozymes predominant in poorly differentiated hepatoma tissue and normal liver tissue, respectively. Inhibition indexes of the

  合成了腺苷5'-磷酸（AMP）在11个位置上具有1-3个原子的取代基或基团取代基的单取代衍生物，并作为大鼠肌肉腺苷酸激酶同工酶（AK-M）的底物和抑制剂进行了研究，并且大鼠AK II和III同工酶分别在低分化肝癌组织和正常肝组织中占优势。对于竞争性抑制，化合物的抑制指数表示为KM（AMP）/ Ki，当仅有KM时，表示为KM（AMP）/ KM。N（1），N6或C（8）或可电离的磷酸氧上的取代基将抑制作用降低到可测量的水平以下; 2'-deoxy-AMP和5'-腺苷对三种同工酶均具有相同的抑制指数。在C（2），O（2'），O（3'），C（4'），C（5'）或O（5' ）对AK-M的抑制指数高于对AK II或III的抑制指数，对AK II和III的抑制指数相同或相似。最有效和/或选择性的抑制剂是2-NHMe-AMP（AK-M指数为0.2； AK-M / AK III指数比为9.1），2'-O-Me-AMP（AK-M指数）
• Thermophilic phosphoribosyltransferases <i>Thermus thermophilus</i> HB27 in nucleotide synthesis
  作者：Ilja V Fateev、Ekaterina V Sinitsina、Aiguzel U Bikanasova、Maria A Kostromina、Elena S Tuzova、Larisa V Esipova、Tatiana I Muravyova、Alexei L Kayushin、Irina D Konstantinova、Roman S Esipov

  DOI：10.3762/bjoc.14.289

  日期：——

  Phosphoribosyltransferases are the tools that allow the synthesis of nucleotide analogues using multi-enzymatic cascades. The recombinant adenine phosphoribosyltransferase (TthAPRT) and hypoxanthine phosphoribosyltransferase (TthHPRT) from Thermus thermophilus HB27 were expressed in E.coli strains and purified by chromatographic methods with yields of 10-13 mg per liter of culture. The activity dependence

  磷酸核糖基转移酶是允许使用多酶级联反应合成核苷酸类似物的工具。来自嗜热栖热菌HB27的重组腺嘌呤磷酸核糖基转移酶（TthAPRT）和次黄嘌呤磷酸核糖基转移酶（TthHPRT）在大肠杆菌菌株中表达并通过色谱法纯化，每升培养物产量为10-13mg。研究了TthAPRT和TthHPRT对不同因素的活性依赖性，以及对不同杂环碱基的底物特异性。确定了具有天然底物的TthHPRT的动力学参数。使用TthAPRT和1-（β-D-呋喃呋喃糖基）吡唑并[3,4-d]嘧啶合成了两个核苷酸：9-（β-D-呋喃呋喃糖基）-2-氯腺嘌呤5'-单磷酸酯（2-Сl-AMP）使用TthНPRT的-4-one 5'-单磷酸盐（Allop-MP）。
• [EN] N-ALKYL-2-SUBSTITUTED ATP ANALOGUES<br/>[FR] ANALOGUES D'ADENOSINE TRIPHOSPHATE (ATB) SUBSTITUES EN POSITION 2 PAR N-ALKYLE
  申请人：ASTRA PHARMACEUTICALS LIMITED

  公开号：WO1994018216A1

  公开（公告）日：1994-08-18

  (EN) There are disclosed compounds of formula (I) wherein R1 and R2 independently represent hydrogen or halogen, R3 and R4 independently represent phenyl, or alkyl C1-6 optionally substituted by one or more substituents selected from OR5, alkylthio C1-6, NR6R7, phenyl, COOR8 and halogen, R5, R6, R7 and R8 independently represent hydrogen or alkyl C1-6, and X represents an acidic moiety, and pharmaceutically acceptable salts thereof. Processes for their production and pharmaceutical compositions and methods of treatment involving their use are also described.(FR) L'invention se rapporte à des composés de la formule (I) dans laquelle R1 et R2 représentent indépendamment hydrogène ou halogène, R3 et R4 représentent indépendamment phényle ou alkyle C1-6 éventuellement substitués par un ou plusieurs substituants choisis entre OR5, alkylthio C1-6, NR6R7, phényle, COOR8 et halogène, R5, R6, R7 et R8 représentent indépendamment hydrogène ou alkyle C1-6, et X représente une fraction acide. L'invention se rapporte également à des sels pharmaceutiquement acceptables de ces composés. Des procédés de production, ainsi que des compositions pharmaceutiques et des procédés de traitement comprenant l'utilisation de ces dernières sont également décrits.

  该文献介绍了公式（I）的化合物，其中R1和R2独立地表示氢或卤素，R3和R4独立地表示苯基或C1-6烷基，该烷基可以选择地被一个或多个取代基所取代，所述取代基选自OR5，C1-6烷基硫基，NR6R7，苯基，COOR8和卤素。R5、R6、R7和R8独立地表示氢或C1-6烷基，X表示酸性基团，以及其药物可接受的盐。该文献还描述了它们的生产过程、药物组合物和涉及其使用的治疗方法。
• N-ALKYL-2-SUBSTITUTED ATP ANALOGUES
  申请人：Astra Pharmaceuticals Limited

  公开号：EP0683789B1

  公开（公告）日：1997-11-05
• ATP analogues
  申请人：Astra Pharmaceuticals Limited

  公开号：EP0508687B1

  公开（公告）日：1995-09-13